|Número de publicación||US4942035 A|
|Tipo de publicación||Concesión|
|Número de solicitud||US 06/716,651|
|Fecha de publicación||17 Jul 1990|
|Fecha de presentación||27 Mar 1985|
|Fecha de prioridad||22 Abr 1982|
|También publicado como||CA1246265A, CA1246265A1, DE3378250D1, EP0092918A2, EP0092918A3, EP0092918B1, US4526938|
|Número de publicación||06716651, 716651, US 4942035 A, US 4942035A, US-A-4942035, US4942035 A, US4942035A|
|Inventores||Jeffrey R. Churchill, Francis G. Hutchinson|
|Cesionario original||Imperial Chemical Industries|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Otras citas (2), Citada por (107), Clasificaciones (58), Eventos legales (3)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
This is a division of application Ser. No. 435,454, filed Apr. 15, 1983, now U.S. Pat. No. 4,526,938.
This invention relates to pharmaceutical compositions of pharmacologically-active polypeptides, which provide continuous release of the polypeptide over an extended period when the composition is placed in an aqueous, physiological-type environment.
It has long been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice, and compositions have already been developed to provide extended release of a number of clinically useful drugs, after oral dosing (see, for example, Remington's Pharmaceutical Sciences, published by Mack Publishing Company, Easton, Penn., U.S.A., 15th Edition, 1975, pages 1618-1631), after parenteral administration (ibidem, pages 1631-1643), and after topical administration (see, for example, United Kingdom Patent Number 1,351,409). A suitable method of parenteral administration is the subdermal injection or implantation of a solid body, for example a pellet or a film, containing the drug, and a variety of such implantable devices have been described. In particular, it is known that, for many drugs, suitable implantable devices for providing extended drug release may be obtained by encapsulating the drug in a biodegradable polymer, or by dispersing the drug in a matrix of such a polymer, so that the drug is released as the degradation of the polymer matrix proceeds.
Suitable biodegradable polymers for use in such substained release formulations are well known, and include polyesters which gradually become degraded by hydrolysis when placed in an aqueous, physiological-type environment. Particular polyesters which have been used are those derived from hydroxycarboxylic acids, and much prior art has been directed to polymers derived from α-hydroxycarboxylic acids, especially lactic acids in both its racemic and optically active forms, and glycolic acid, and copolymers thereof - see, for example, U.S. Pat. Nos. 3,773,919 and 3,887,699; Jackanicz et al., Contraception, 1973, 8, 227-234; Anderson et al., ibidem, 1976, 11, 375-384; Wise et al., Life Sciences, 1976, 19, 867-874; Woodland et al., Journal of Medicinal Chemistry, 1973, 16, 897-901; Yolles et al., Bulletin of the Parenteral Drug Association, 1976, 30, 306-312; Wise et al., Journal of Pharmacy and Pharmacology, 1978, 30, 686-689 and 1979, 31, 201-204.
United Kingdom Patent Specification Number 1,325,209 (equivalent to U.S. Pat. No. 3,773,919) and U.S. Pat. No. 3,887,669 make reference to extended or sustained release of polypeptides. The latter mentions insulin only, but it contains no specific example of any such formulation, and the reference to polypeptides is apparently entirely speculative, appearing, as it does, only in an extensive listing of very many different classes of drugs which can allegedly be incorporated into formulations of the kind described therein. In fact, essentially all of the other drug types referred to in that specification, apart from polypeptides, are relatively hydrophobic in character and of relatively low molecular weight, and the disclosure of that specification displays no recognition of the difficulties which we have encountered when seeking to obtain satisfactory sustained release formulations of polypeptides, many of which are relatively hydrophilic, and of relatively high molecular weight.
It is to be appreciated that "sustained" or "extended" release of a drug may be either continuous or discontinuous. We have now discovered, in fact, that in many cases when the teaching of the prior art, and in particular the teaching of United Kingdom Specification No. 1,325,209, is applied to the manufacture of a formulation of a polypeptide, the release of the polypeptide from the formulation, although occurring over an extended period of time, may also be discontinuous. For example, the release of a polypeptide from a polylactide polymer as described in the said Specification is often preceded by a significant induction period, during which no polypeptide is released, or is polyphasic, and comprises an initial period during which some polypeptide is released, a second period during which little or no poly-peptide is released, and a third period during which most of the remainder of the polypeptide is released. By contrast, it is an object of the present invention to provide compositions of polypeptides from which, apart possibly from a relatively short initial induction period, the polypeptide is released continuously, with no periods during which little or no polypeptide is released. The words "continuous release" are used in this specification solely to describe a release profile which is essentially monophasic, although it may have a point of inflection, but certainly has no "plateau" phase.
United Kingdom Patent Specification Number 1,388,580 describes sustained release formulations containing insulin, which are based on hydrogels formed by reacting a water soluble polymer with a chelating agent, then cross linking the polymer-chelating agent chains by reaction with a polyvalent metal ion in aqueous solution to form a hydrogel. Insulin was incorporated in a preformed hydrogel in aqueous solution, and the whole was homogenised and injected sub-cutaneously or intramuscularly.
It is an object of the present invention to provide an implantable or injectable pharmaceutical or veterinary formulation for pharmacologically useful polypeptides, which is in solid form, and which absorbs water from the animal body, after implantation, to form a hydrogel from which the polypeptide is released continuously over an extended period of time.
Thus, according to the present invention, there is provided a pharmaceutical composition comprising a pharmacologically useful polypeptide and a pharmaceutically or veterinarily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer, which has a minimum weight average molecular weight of 5,000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable, the composition being capable of absorbing water to form a hydrogel when placed in water or an aqueous physiological type environment.
This invention is applicable to polypeptides quite generally, without any limitation as to structure or molecular weight, but is most useful for polypeptides which are relatively hydrophilic, and the following list, which is not intended to be exhaustive, is indicative of polypeptides which may be employed in the formulation of this invention: oxytocin, vasopressin, adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF), prolactin, luliberin or luteinizing hormone releasing hormone (LH-RH), growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidin, gramicidines, and synthetic analogues and modifications and pharmaceutically-active fragments thereof, monoclonal antibodies and soluble vaccines.
A particular LH-RH analogue to which this invention is applicable is ICI.118,630, Glu-His-Trp-Ser-Tyr-D-Ser(O-tBu)-Leu-Arg-Pro-Azgly-NH2.
By "an aqueous physiological type environment" we mean the body, particularly the musculature or the circulatory system, of a warm-blooded animal, although in laboratory investigations such an environment may be mimicked by aqueous liquids, optionally buffered to a physiological pH, at a temperature of between 35° and 40° C.
The continuous release composition of the invention may be placed in the body of an animal which it is desired to treat with a polypeptide by, for example, intramuscular or subcutaneous injection, or by sub-dermal surgical implantation, in conventional clinical or veterinary manner.
The pharmaceutically or veterinarily acceptable amphipathic copolymer may be, for example, a linear block copolymer of the formula Am (BA)n or Bm (AB)n wherein m is 0 or 1, n is an integer, A is a pharmaceutically or veterinarily acceptable hydrophobic polymer and B is a pharmaceutically or veterinarily acceptable hydrophilic polymer, or the amphipathic copolymer may be a graft or branched block copolymer of the formula ABn or BAn wherein A, B and n have the meanings stated above, and wherein respectively either A or B is a backbone polymer with n units of a monomer or polymer B or A respectively grafted onto it.
The pharmaceutically or veterinarily acceptable hydrophobic polymer A may be, for example, poly-(D-, L- or DL-lactic acid), poly(D-, L- or DL-lactide), polyglycolic acid, polyglycolide, poly-ε-caprolactone, poly(3-hydroxybutyric acid) or a non-therapeutic hydrophobic polypeptide, for example polybenzylglutamate. Alternatively, the hydrophobic polymer A may be a polyacetal of the general formula: ##STR1## wherein R is a hydrocarbon radical, or a polycarbonate or polyorthoester of the general formula: ##STR2## wherein R is a hydrocarbon radical, as described in U.S. Pat. No. 4,093,709, which is incorporated herein by reference, or it may be a copolymer comprising such acetal, carbonate, or ortho-ester units alternating with diol units, or it may be a copolymer of the formula: ##STR3## which is obtained by reacting pentaerythritol with ketene to form 3,9-bis(methylene)-2,4,8,10-tetraoxaspiro[5,5]undecane which is then copolymerised with a diol HO-R-OH, as described in Journal of Polymer Science, Polymer Letters, 1980, pages 619-624. The diol HO-R-OH may be, for example, a high molecular weight polyethylene glycol or a mixture of that with low molecular weight species, giving a random structure. The hydrophobic polymer may also itself be a copolymer derived from two or more monomers from which the above polymers are derived.
The pharmaceutically or veterinarily acceptable hydrophilic polymer B may be, for example, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, polyacrylamide, polymethacrylamide, dextran, alginic acid, sodium alginate, gelatine or a copolymer of two or more of the monomers from which the above polymers are derived.
In a further alternative, the hydrophilic polymer B may itself be a copolymer, for example a polyoxyethylene/polyoxypropylene block copolymer of the type known as "Pluronics" (trade mark) or "Synperonics" (trade mark).
Various mechanisms by which drugs are released from biocrodible polymers are described in "Controlled Release of Biactive Materials", edited by R. Baker, Academic Press 1980, particularly chapter 1, pages 1-17, by J. Heller and R. W. Baker.
In the present invention, when the dry amphipathic copolymer, containing a polypeptide, is immersed in water or placed in an aqueous physiological environment within an animal body, water uptake is a function of the hydrophilic or water-interactive parts of the copolymer, and the material swells. This absorption of water, however, renders the water-insoluble parts of the copolymer incompatible, and these hydrophobic parts of the copolymer then serve as cross-linking points, which thus serve to limit further water uptake. In this swollen, hydrated state, the matrix is permeable to water-soluble polypeptides incorporated within the matrix, and such polypeptides are thus progressively desorbed from the matrix.
In the process of swelling, and when swollen to some equilibrium state, hydrolytic degradation of the hydrophobic part of the copolymer starts to occur. The partially degraded copolymer has greater swellability, so that continued hydrolysis leads to progressively further water uptake, an increasingly water-permeable matrix, and a further increase in polypeptide desorption which compensates for its decreasing concentration and maintains its continuous release. Thus, by appropriate design of the copolymer material, the initial swelling to a hydrogel and consequent desorption of active material, and the rate of subsequent hydrolytic degradation to increase the further desorption of active material to compensation for its decreasing concentration in the matrix, can be controlled so as to give continuous release of active material over an extended period of time, as defined above.
Such an ideal release profile for the active material can also be obtained by blending different copolymers, each having its own defined properties (for example, molecular weight, molecular weight distribution, block structure, hydrophilicity, degradation properties, diffusional properties), and by appropriate combination of different such materials, the rate of release, and the duration of release, of an active material can be varied as desired.
Also by appropriate choice of the above parameters, and/or appropriate blending, a copolymer material can be obtained which allows of processing into implants at relatively low temperatures, certainly below 100° C., and in some cases even at room temperature, and is thus suitable for the fabrication of implants incorporating heat sensitive or solvent sensitive polypeptide active materials. For example, block copolymers of polyethylene glycol and amorphous hydrophobic polymers, having a glass transition temperature above 37° C., are particularly useful, because the polyethylene glycol block plasticises the hydrophobic block, giving a material which is readily processed at relatively low, even at room temperature, while on subsequent standing the polyethylene glycol blocks crystallise to give a tough hard product which can be easily handled.
The block copolymers defined above are themselves novel, useful materials, per se. Thus, according to a further feature of the invention, there is provided a pharmaceutically or veterinarily acceptable amphipathic linear, branched or graft block copolymer, which has a minimum weight average molecular weight of 5,000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable, and which copolymer is capable of absorbing water to form a hydrogel when placed in water on an aqueous environment.
Particular such copolymers are those defined above.
According to a further feature of the invention, there is provided a blend of two or more such copolymers as defined above.
These copolymers and copolymer blends are also useful more generally for the continuous release of non-peptide drugs by oral, including intra-ruminal, parenteral, ocular, rectal or vaginal administration.
Thus, according to further features of this invention there are provided pharmaceutical or veterinary compositions comprising a non-peptide pharmacologically-active compound and a block copolymer as defined above, and the use of such block copolymers for the continuous release of such a non-peptide, pharmacologically-active compound.
According to a further feature of the invention, there is provided a process for the manufacture of a pharmaceutically or veterinarily acceptable amphipathic linear, branched or graft block copolymer as defined above, which comprises copolymerising monomer A and monomer B by conventional techniques such as graft copolymerisation, polycondensation and polyaddition, optionally with an appropriate catalyst, for example zinc oxide, zinc carbonate, basic zinc carbonate, diethyl zinc, organotin compounds, for example stannous octoate (stannous 2-ethylhexanoate), tributylaluminium, titanium, magnesium or barium compounds or litharge, and of these stannous octoate is generally preferred.
The copolymerisations are otherwise carried out in conventional manner, known in the polymer art, as regards time and temperature.
The invention is illustrated but not limited by the following Examples:
Polyethylene glycol of molecular weight 20,000 (30 g.) was stirred and heated under vacuum (<0.1 mm. of mercury) at 120° C. for 3 hours. D,L-lactide (15 g.) and glycolide (15 g.) were added, and the mixture was stirred under a nitrogen atmosphere until the solids melted. The temperature was raised to 160° C., and stannous octoate (stannous 2-ethylhexanoate) (0.1 ml.) was added. The mixture was maintained at 160° C. for 3 hours, by which time it had become highly viscous, and it was then cooled and dissolved in acetone (200 ml.). This acetone solution was added slowly to vigorously stirred ethanol (1500 ml.), and the precipitate thus produced was filtered off, and dried in a vacuum oven for 3 hours at room temperature, then overnight at 40° C.
The n.m.r. spectrum of this copolymer, in deuteriochloroform, showed it to have the composition oxyethylene:lactic:glycolic of 2:1:1.
This copolymer was moulded at about 60° C. to a soft, plastic transparent film. A sample (39 mg.) swelled rapidly when placed in water, taking up 135 mg. of water over 4 hours, to give a transparent hydrogel which subsequently disintegrated over 2 weeks at 37° C.
The polymer described in Example 1 (20.2 mg.) and bovine growth hormone (BGH), (5.1 mg.) were blended together at about 40° C. to give an opaque blend, which was moulded into a slab 1 mm. thick. This slab was immersed in a buffer solution at pH 8.6 (M/15 buffer, pH 8.6, containing 0.01% sodium azide), and released a material of molecular weight about 22,000 which had the same retention time on high pressure liquid chromatography as BGH, over a period of at least 12 days.
Using the process described in Example 2, the copolymer/BGH blend was formed into discs weighing about 45 mg. and containing about 20% of BGH. When such discs were implanted, each in a hypophysectomised rat, the animals' weights increased by an average of 25% over 7 days, whereas the weights of control animals each given a placebo implant remained virtually unchanged.
The copolymer described in Example 1 (13.5 mg.) and monoclonal mouse immunoglobulin A, (IgA), with a defined antigen specificity and a molecular weight of >180000 (1.5 mg.) were blended at 50° C. to give a homogeneous mixture of the IgA in the copolymer, and the protein/copolymer mixture was moulded to give a sphere of ˜2 mm. diameter. The in vitro release of IgA was evaluated by immersing the protein copolymer in buffer (phosphate buffered saline, pH 7.2) at 37° C. Using an enzyme linked immunoassay technique the aqueous medium was assayed for active IgA, and release of the biologically active protein was shown to start after 2 days and continue for at least 9 days.
Polyethylene glycol having a molecular weight of 20000 (50 g.) was dissolved in chloroform (150 mg.) and washed six times with distilled water (˜300 ml.), discarding the aqueous washes. The chloroform was evaporated under reduced pressure and the purified polyethylene glycol was dried at 160° C./0.05 mm. Hg. for 1 hr.
Stannous octoate (stannous 2-ethylhexanoate) (˜5 g.) was purified by heating at 140° C./0.055 mm. Hg. to remove impurities. The purified polyethylene glycol (14.3 g.) was heated to 160° C. under vacuum (0.05 mm. Hg.) in a 100 ml. round bottomed flask for 1 hr. Freshly prepared, pure D,L-lactide (42.9 g.) was added under nitrogen and melted at 160° C. Stannous octoate (0.2 ml.) was added, and the mixture was stirred until the viscosity no longer allowed stirring to continue. After 3 hrs., a highly viscous product was obtained. The mixture was allowed to cool, the flask was broken, the contents of the flask were dissolved in acetone (˜300 ml.) and the solution was filtered. The filtrate was added slowly to ethanol (˜1000 ml.) with vigorous agitation to give a fibrous precipitate, which was collected and dried at 30° C. in a vacuum oven overnight. Analysis of the product by n.m.r. showed the product to have a composition of oxyethylene:lactic of 1:3, and the intrinsic viscosity in chloroform was 1.055.
The product was moulded to a thin (0.2 mm.), soft, plastic transparent film. On immersion in water, the film (0.54 g.) increased in weight to 0.95 g. in 1 day at 37° C. The hydrated transparent film had rigidity and strength superior to the initially dry copolymer. After 35 days, the film was intact and retained good mechanical properties showing that the copolymer was being degraded only slowly, as shown by change of composition by n.m.r.
When bovine growth hormone is incorporated into the dry copolymer at 60° C., the resulting polypeptide/polymer blend releases a 22000 molecular weight product into buffer (M/15 phosphate buffer, pH 8.6) over at least 7 days.
Polyethylene glycol having a molecular weight of 6000 (50 g.) was purified using the method described above in Example 5.
The purified dry polyethylene glycol (7.5 g.) and stannous chloride dihydrate (15 mg.) were mixed at room temperature then heated with stirring to 155° C. under high vacuum (0.1-0.01 mm. Hg.) and maintained at this temperature for 2 hrs. while freshly prepared, dry D,L-lactide (22.5 g.) was added to the mixture under nitrogen, and melted. The reaction temperature was maintained at 155°-160° C. for 3 hrs. to give a viscous product, which was poured onto poly-tetrafluoroethylene film and allowed to cool. The polymeric product was dissolved in acetone (70 ml.) with warming, and the polymer was isolated by pouring the acetone solution into ethanol (600 ml.). The precipitate was dried in a vacuum oven overnight at 60° C. The polymer had an intrinsic viscosity in chloroform of 0.41. When pressed as a thin film (0.2 mm.) and immersed in water, the polymer takes up approximately its own weight of water at 37° C. over 24 hrs. to give a tough hydrogel.
99 Mg. of a block copolymer as prepared in Example 6 containing 25 parts of polyethylene glycol (mol. wt. 6000) and 75 parts of poly(D,L-lactide) was dissolved in 4.5 ml. of anhydride free glacial acetic acid and 0.5 ml. of distilled water. 200 μL. of a solution containing 1.1 mg. of mouse epidermal growth factor (EGF) was added to the polymer solution, and the mixture was homogenised. The homogenised solution was frozen and then freeze dried for 18 hrs., the product was moulded at 50° C. to give an implant weighing 40 mg. (˜8 mm.×4 mm.×1 mm). The implant was placed in 1 ml. of human serum at 37° C., and the release of EGF was measured by radio immunoassay on aliquots of serum. The results showed a continuous release of peptide over at least three days.
25 G. of a copolymer containing equimolar proportions of D,L-lactide and glycolide and having an intrinsic viscosity in chloroform of 0.20 was dissolved in 50 ml. of dry ethyl ecetate, and the solution was heated to reflux with stirring under nitrogen. 0.25 G. of lauroyl peroxide was dissolved in freshly distilled vinyl pyrrolidone (25 ml.). The mixture was added dropwise to the refluxing polymer over 2 hrs., and the mixture was heated at reflux for a further 6 hrs. On cooling, the mixture gelled. Purification of the amphipathic block graft copolymer by removal of homo polymer of polyvinyl pyrrolidone using precipitation techniques was difficult as precipitation often resulted in colloidal suspensions, and this indicated that grafting of polyvinyl pyrrolidone to the lactide/glycolide copolymer had occurred.
The ethyl acetate mixture was therefore warmed to 70° C. and 50 ml. of ethanol was added to give a colloidal suspension, from which the polymer was isolated by precipitation into n-hexane (2 liters). The polymer thus obtained was dried at 90° C. overnight under vacuum to give on cooling a brittle product consisting of graft copolymer and homo polyvinylpyrrolidone. The product had an intrinsic viscosity of 0.29 in chloroform, and approximately 50% of polyvinyl-pyrrolidone as homo-copolymer and graft block copolymer.
The polymer thus obtained (0.45 g.) and ICI. 118,630 (0.05 g.) were dissolved in anhydride-free glacial acetic acid (5 ml.) and freeze dried at 0.01 mm. of mercury for 22 hr.
The product was moulded at 110° C. for 20 secs. to give a slab (˜0.8 cm.×1.2 mm.×2 mm., weighing 30 mg.) which, when immersed in aqueous pH 7.4 buffer at 37° C. released the peptide over a period of several days.
50 G. of polyvinyl alcohol having a molecular weight of 14,000 was dissolved in 500 g. of commercial D,L-lactic acid (containing ˜12% water) with stirring under nitrogen. The mixture was heated to 140° C. and water was distilled off over 8 hrs., during which time the mixture became progressively more viscous and its temperature rose to 190° C. When no further water distilled over, the pressure was reduced to ˜25 cm. of mercury, and the mixture was heated for a further 8 hrs. Finally, the pressure was reduced to 0.1 mm. of mercury and the mixture was heated at 200° C. for 8 hrs. to give a highly viscous amber product.
The polymer was allowed to cool, and the flask was broken. The product was broken up into small pieces and dissolved in methanol (1.5 liters), and the product was isolated by precipitate in 10 liters of distilled water. The precipitation was washed with a further 5 liters of water, and dried under vacuum at room temperature for 8 hrs., finally at 100° C. for 16 hrs., to give an amber glassy product which consisted of a polyvinyl alcohol back-bone containing pendant polylactic acid chains of low molecular weight, intrinsic viscosity=0.65 in chloroform. The product contained approximately 85% of polylactic acid, and the pendant polylactic acid average chain length was approximately 3.5.
The polymer was moulded at 100° C. to give a slab 1 cm.×0.2 cm.×0.2 cm. which was immersed in water at 37° C. The product absorbed water and became flexible, and eroded to give soluble products over a period of 2 months.
Mouse epidermal growth factor (285 μl. of a 21 mg./ml. solution in distilled water) was added to a solution of an 80/20 poly(D,L-lactide)/PEG 6000 copolymer of intrinsic viscosity 0.36 in chloroform, (45 mg.) in 2.5 ml. of 90% aqueous acetic acid. The solution of peptide and polymer was frozen and then freeze dried at ˜0.01 mm. Hg. for 24 hours to give a dried product. The freeze dried material was moulded at 60° C. to give implants weighing 13.5 mg. and 15.3 mg. containing 1.3 and 1.5 mg. of peptide respectively.
These were implanted subcutaneously into 2 cats, each fitted with a gastric fistula. Blood samples were taken, and gastric acid output in response to a histamine stimulus was measured. Peptide was detected in the blood by radioimmunassay for a minimum of 3 days subsequent to implantation, and gastric acid output showed inhibition of 3-6 days subsequent to implantation.
Mouse epidermal growth factor (120 μl. of 10.5 mg. peptide in 320 l. of distilled water) was added to a solution of an 85/15 poly(D,L-lactide)/PEG 6000 copolumer of intrinsic viscosity 0.39 in chloroform, (36 mg.) in 1.8 ml. of 90% aqueous acetic acid. The resultant solution was frozen and freeze-dried overnight. The freeze dried material was moulded at 70° C. to give an implant weighing 16.9 mg. (dimensions approximately 1×1×5 mm.).
Peptide was released from this implant continuously over at least 15 days into 10% human serum in water containing 0.1% sodium azide.
To show the effect of composition and hydrophilicity of the block copolymer on release of polypeptide from implants the following comparison was carried out.
In separate experiments implants were prepared using
(a) a block copolymer of intrinsic viscosity 0.39 in chloroform containing 25% w/w polyethylene glycol having a molecular weight of 6000 and 75% w/w of poly(D,L-lactide).
(b) a block copolymer of intrinsic viscosity 0.79 in chloroform containing 5% w/w polyethylene glycol having a molecular weight of 6000 and 95% w/w of poly(D,L-lactide).
76.2 mg. of polymer and ICI 118,630 (23.8 mg. as the acetate salt, equivalent to 20 mg. pure peptide) were dissolved in anhydride-free glacial acetic acid (1.5 ml.). The solution was frozen and freeze dried for 18 hours, and the freeze dried product was moulded at ˜70° C. to give implants weighing ˜45-50 mg. (dimensions approximately 0.2 cm.×0.2 cm.×1 cm.).
The implants were immersed in 1 ml. of McIlvains pH 7.4 buffer at 37° C., and 1 ml. samples of the aqueous medium were removed at given time points and assayed by high pressure liquid chromatography for drug content. The aqueous medium removed was replaced each time by 1 ml. of fresh buffer.
These release experiments showed that implants prepared using the more hydrophilic is polymer, containing 25% polyethylene glycol, released compounds for ˜18 days.
In contrast, the implant prepared using the less hydrophilic copolymer, containing 5% polyethylene glycol, released compound continuously for at least 250 days.
Poly(ethylene glycol methyl ether) having a molecular weight of 5000 was purified as in Example 5.
20 G. of the purified poly(ethylene glycol methyl ether) was dried at 160° C./0.01 mm. Hg. for 1 hour. 80 G. of dry, freshly prepared D,L-lactide were added and the mixture stirred under a nitrogen atmosphere at 160° C. When all the D,L-lactide had melted, 0.15 ml. of stannous octoate (stannous-2-ethylhexanoate) were added, and the mixture was maintained at 160° C. for 6 hours, during which time a highly viscous product was formed. The mixture was allowed to cool, the flask was broken and the contents were dissolved in 200 ml. of acetone. The actone solution of polymer was added with vigorous stirring to 2000 ml. of hexane to precipitate the polymer. The precipitated polymer was dried at 70° C. under reduced pressure for 24 hours to give a block copolymer having an AB structure where A is polylactide and B is poly(ethylene glycol methyl ether).
This copolymer is particularly useful for preparing water-in-oil dispersions, which can be used to prepare microcapsules, or in microencapsulation procedures.
For example, 5 g. of the copolymer was dissolved in 200 ml. of methylene chloride, and 1 ml. of an aqueous solution of ICI.118,630 containing 20 mg. of compound was added with vigorous stirring, to produce a stable water in oil dispersion.
The water-in-oil emulsion was stirred vigorously and a non-solvent, such as hexane (2000 ml.) was added slowly to produce microcapsules, which were isolated by filtration, and dried, to give a drug/polymer mixture which even in this microcapsule or microencapsulated form gives sustained release over a period of several days.
The poly(ethylene glycol methyl ether) used in the above process was replaced by other derivatives of pol (ethylene glycol) to prepare similar block copolymers, and suitable examples are the monocetyl ethers (ceto macrogols) and stearate esters.
|1||Das, "Controlled Release Technology" John Wiley and Sons, Inc. 1983 pp. 9-10.|
|2||*||Das, Controlled Release Technology John Wiley and Sons, Inc. 1983 pp. 9 10.|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US5225205 *||18 Feb 1992||6 Jul 1993||Debiopharm S.A.||Pharmaceutical composition in the form of microparticles|
|US5320840 *||22 Jul 1991||14 Jun 1994||Imperial Chemical Industries Plc||Continuous release pharmaceutical compositions|
|US5352515 *||2 Mar 1992||4 Oct 1994||American Cyanamid Company||Coating for tissue drag reduction|
|US5410016 *||1 Mar 1993||25 Abr 1995||Board Of Regents, The University Of Texas System||Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers|
|US5444113 *||29 Sep 1993||22 Ago 1995||Ecopol, Llc||End use applications of biodegradable polymers|
|US5462990 *||5 Oct 1993||31 Oct 1995||Board Of Regents, The University Of Texas System||Multifunctional organic polymers|
|US5476909 *||7 Feb 1994||19 Dic 1995||Sam Yang Co., Ltd.||Biodegradable copolymer for medical application|
|US5530074 *||7 Jun 1995||25 Jun 1996||American Cyanamid Company||Coating for tissue drag reduction|
|US5548035 *||4 May 1994||20 Ago 1996||Sam Yang Co., Ltd.||Biodegradable copolymer as drug delivery matrix comprising polyethyleneoxide and aliphatic polyester blocks|
|US5567435 *||6 Jun 1995||22 Oct 1996||Board Of Regents, The University Of Texas System||Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers|
|US5573934 *||1 Mar 1993||12 Nov 1996||Board Of Regents, The University Of Texas System||Gels for encapsulation of biological materials|
|US5618850 *||9 Mar 1995||8 Abr 1997||Focal, Inc.||Hydroxy-acid cosmetics|
|US5621050 *||7 Jun 1995||15 Abr 1997||American Cyanamid Company||Coating for tissue drag reduction|
|US5626863 *||27 Ene 1995||6 May 1997||Board Of Regents, The University Of Texas System||Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers|
|US5627233 *||6 Jun 1995||6 May 1997||Board Of Regents, The University Of Texas System||Multifunctional organic polymers|
|US5760118 *||5 Jun 1995||2 Jun 1998||Chronopol, Inc.||End use applications of biodegradable polymers|
|US5766704 *||13 Mar 1996||16 Jun 1998||Acushnet Company||Conforming shoe construction and gel compositions therefor|
|US5773019 *||27 Sep 1995||30 Jun 1998||The University Of Kentucky Research Foundation||Implantable controlled release device to deliver drugs directly to an internal portion of the body|
|US5785993 *||29 Jul 1996||28 Jul 1998||Focal, Inc.||Reduction of adhesions using controlled delivery of active oxygen inhibitors|
|US5858746 *||25 Ene 1995||12 Ene 1999||Board Of Regents, The University Of Texas System||Gels for encapsulation of biological materials|
|US5879688 *||30 Oct 1996||9 Mar 1999||Focal, Inc.||Hydroxy-acid cosmetics|
|US5904935 *||7 Jun 1995||18 May 1999||Alza Corporation||Peptide/protein suspending formulations|
|US5939157 *||30 Oct 1995||17 Ago 1999||Acushnet Company||Conforming shoe construction using gels and method of making the same|
|US5955159 *||27 Oct 1995||21 Sep 1999||Acushnet Company||Conforming shoe construction using gels and method of making the same|
|US5972370 *||28 Ene 1999||26 Oct 1999||Alza Corporation||Peptide/protein suspending formulations|
|US5985383 *||14 Mar 1996||16 Nov 1999||Acushnet Company||Conforming shoe construction and gel compositions therefor|
|US6060582 *||4 Ago 1998||9 May 2000||The Board Of Regents, The University Of Texas System|
|US6083524||6 Oct 1997||4 Jul 2000||Focal, Inc.||Polymerizable biodegradable polymers including carbonate or dioxanone linkages|
|US6177095||7 Ene 2000||23 Ene 2001||Focal, Inc||Polymerizable biodegradable polymers including carbonate or dioxanone linkages|
|US6197350 *||18 Dic 1997||6 Mar 2001||Takeda Chemical Industries, Ltd.||Method of producing a sustained-release preparation|
|US6258382||10 Ene 2000||10 Jul 2001||Takai Chemical Co.||Drug sustained-released biomaterial|
|US6261544||15 Feb 1999||17 Jul 2001||Focal, Inc.||Poly(hydroxy acid)/polymer conjugates for skin applications|
|US6306922||26 Ene 2000||23 Oct 2001||Boards Of Regents, The University Of Texas System|
|US6399103 *||14 Nov 2000||4 Jun 2002||Takeda Chemical Industries, Inc.||Method of producing a sustained-release preparation|
|US6465001||3 Mar 1998||15 Oct 2002||Board Of Regents, The University Of Texas Systems||Treating medical conditions by polymerizing macromers to form polymeric materials|
|US6521431||22 Jun 1999||18 Feb 2003||Access Pharmaceuticals, Inc.||Biodegradable cross-linkers having a polyacid connected to reactive groups for cross-linking polymer filaments|
|US6602975||22 Oct 2001||5 Ago 2003||Board Of Regents, The University Of Texas System|
|US6632446||23 Oct 2000||14 Oct 2003||The Board Of Regents, University Of Texas System||Coating substrates by polymerizing macromers having free radical-polymerizable substituents|
|US6649168||17 Sep 2001||18 Nov 2003||Novartis Ag||Pharmaceutical compositions comprising TGF-beta|
|US6780427||27 Jul 1998||24 Ago 2004||Genzyme Corporation||Reduction of adhesions using controlled delivery of active oxygen inhibitors|
|US6828303||31 Ago 2001||7 Dic 2004||Scios, Inc.||Prolonged delivery of peptides|
|US6927282 *||27 Ago 2001||9 Ago 2005||Monsanto Technology Llc||Clarification of protein precipitate suspensions using anionic polymeric flocculants|
|US7087244 *||16 Abr 2002||8 Ago 2006||Battelle Memorial Institute||Thermogelling oligopeptide polymers|
|US7153519||25 Jun 2003||26 Dic 2006||Board Of Regents, The University Of Texas System||Implantable substrate coated with a macromer having free radical polymerizable substituents|
|US7193007 *||15 Mar 2001||20 Mar 2007||Yu-Ling Cheng||Environment responsive gelling copolymer|
|US7282216||12 Nov 2002||16 Oct 2007||Alkermes Controlled Therapeutics, Inc.||Biocompatible polymer blends and uses thereof|
|US7649023||28 Jun 2002||19 Ene 2010||Novartis Ag||Biodegradable block copolymeric compositions for drug delivery|
|US7786220||26 Ene 2005||31 Ago 2010||Sungyunkwan University Foundation For Corporate Collaboration||pH and temperature sensitive hydrogels|
|US8246990||3 May 2006||21 Ago 2012||Suprapolix B.V.||Hydrogen bonded hydrogels|
|US8247524||19 Oct 2010||21 Ago 2012||Suprapolix B.V.||Preparation of supramolecular polymers containing quadruple hydrogen bonding units in the polymer backbone|
|US8263108||21 Jun 2002||11 Sep 2012||Durect Corporation||Zero-order prolonged release coaxial implants|
|US8268952||11 Jul 2005||18 Sep 2012||Suprapolix B.V.||Supramolecular ionomers|
|US8323693||12 Mar 2003||4 Dic 2012||Medrx Co., Ltd.||External preparation for wounds|
|US8628789||21 Mar 2008||14 Ene 2014||Suprapolix, B.V.||Strong reversible hydrogels|
|US8642666||24 Jun 2009||4 Feb 2014||Protherics Salt Lake City, Inc.||Biodegradable block copolymeric compositions for drug delivery|
|US8647657||31 Jul 2007||11 Feb 2014||Durect Corporation||Polymeric devices for controlled release of active agents|
|US8722078||31 Jul 2007||13 May 2014||Durect Corporation||Polymeric device for controlled release of active agents|
|US8754213||6 Jul 2009||17 Jun 2014||Suprapolix B.V.||High flow supramolecular compounds|
|US8795727||5 Nov 2010||5 Ago 2014||Spotlight Technology Partners Llc||Fragmented hydrogels|
|US8835492||31 Mar 2006||16 Sep 2014||Sungyunkwan University Foundation For Corporate Collaboration||Temperature and pH sensitive block copolymer and polymeric hydrogels using the same|
|US8883188||3 May 2006||11 Nov 2014||Suprapolix B.V.||Modular bioresorbable or biomedical, biologically active supramolecular materials|
|US8889174||20 Ago 2012||18 Nov 2014||Durect Corporation||Zero-order prolonged release coaxial implants|
|US8889826||1 Jul 2005||18 Nov 2014||Biosource Pharm, Inc.||Peptide antibiotics and methods for making same|
|US8906866||15 Mar 2013||9 Dic 2014||Biosource Pharm, Inc.||Antibiotic compositions for the treatment of gram negative infections|
|US8916615||7 Feb 2013||23 Dic 2014||Research & Business Foundation Sungkyunkwan University||PH-sensitive polymer hydrogel with dual ionic transition and use thereof|
|US8937040||21 Dic 2012||20 Ene 2015||Biosource Pharm, Inc.||Antibiotic compositions for the treatment of gram negative infections|
|US9006364||18 Oct 2013||14 Abr 2015||Suprapolix B.V.||Supramolecular polymers from low-melting, easily processable building blocks|
|US9006386||4 Nov 2011||14 Abr 2015||Suprapolix B.V.||Process for the preparation of a supramolecular polymer|
|US9265836||23 Dic 2013||23 Feb 2016||Protherics Salt Lake City, Inc.||Biodegradable block copolymeric compositions for drug delivery|
|US9289449||23 Jul 2014||22 Mar 2016||Spotlight Technology Partners Llc||Hydrogel compositions|
|US9339586||29 Oct 2014||17 May 2016||Suprapolix B.V.||Modular bioresorbable or biomedical, biologically active supramolecular materials|
|US9469728||5 Sep 2008||18 Oct 2016||Sungkyunkwan University Foundation For Corporate||Temperature and pH-sensitive block copolymer having excellent safty in vivo and hydrogel and drug delivery system using thereof|
|US20030007992 *||21 Jun 2002||9 Ene 2003||Southern Biosystems, Inc.||Zero-order prolonged release coaxial implants|
|US20030078339 *||27 Ago 2002||24 Abr 2003||Kiser Patrick F.||Degradable cross-linking agents and cross-linked network polymers formed therewith|
|US20030133980 *||12 Nov 2002||17 Jul 2003||Alkermes Controlled Therapeutics, Inc.||Biocompatible polymer blends and uses thereof|
|US20040001872 *||28 Jun 2002||1 Ene 2004||Chung Shih||Biodegradable block copolymeric compositions for drug delivery|
|US20040023987 *||13 Jun 2001||5 Feb 2004||Yoshio Hata||Sustained release compositions|
|US20040077780 *||16 Abr 2002||22 Abr 2004||Battelle Memorial Institute||Thermogelling oligopeptide polymers|
|US20040086493 *||25 Jun 2003||6 May 2004||Board Of Regents, The University Of Texas System||Gels for encapsulation of biological materials|
|US20040185101 *||11 Dic 2003||23 Sep 2004||Macromed, Incorporated.||Biodegradable triblock copolymers as solubilizing agents for drugs and method of use thereof|
|US20040228794 *||19 Feb 2004||18 Nov 2004||Battelle Memorial Institute||Therapeutic agent carrier compositions|
|US20050020719 *||15 Mar 2001||27 Ene 2005||Yu-Ling Cheng||Environment responsive gelling copolymer|
|US20050042293 *||25 Nov 2003||24 Feb 2005||The University Of British Columbia||Polymeric systems for drug delivery and uses thereof|
|US20050118269 *||12 Mar 2003||2 Jun 2005||Hidetoshi Hamamoto||External preparation for wounds|
|US20060003918 *||7 Dic 2004||5 Ene 2006||Yesook Kim||Prolonged delivery of peptides|
|US20060200233 *||6 Ene 2006||7 Sep 2006||Scimed Life Systems, Inc.||Optimally expanded, collagen sealed ePTFE graft with improved tissue ingrowth|
|US20080207874 *||1 Jul 2005||28 Ago 2008||Biosource Pharm, Inc.||Peptide Antibiotics and Methods For Making Same|
|US20080260795 *||21 Mar 2008||23 Oct 2008||Suprapolix B.V.||Strong reversible hydrogels|
|US20080287633 *||18 May 2007||20 Nov 2008||Drumheller Paul D||Hydrogel Materials|
|US20080293827 *||31 Mar 2006||27 Nov 2008||Sungkyunkwan University Foundation For Coroporate Collaboration||Temperature and Ph Sensitive Block Copolymer and Polymeric Hydrogels Using the Same|
|US20090004272 *||31 Jul 2007||1 Ene 2009||Durect Corporation||Polymeric devices for controlled release of active agents|
|US20090004273 *||31 Jul 2007||1 Ene 2009||Durect Corporation||Polymeric device for controlled release of active agents|
|US20090004274 *||3 May 2006||1 Ene 2009||Suprapolix B.V.||Hydrogen Bonded Hydrogels|
|US20090111930 *||11 Jul 2005||30 Abr 2009||Suprapolix B. V.||Supramolecular Ionomers|
|US20090130172 *||3 May 2006||21 May 2009||Patricia Yvonne Wilhelmina Dankers||Modular Bioresorbable or Biomedical, Biologically Active Supramolecular Materials|
|US20090264537 *||24 Jun 2009||22 Oct 2009||Protherics Salt Lake City, Inc.||Biodegradable block copolymeric compositions for drug delivery|
|US20100076067 *||30 Nov 2009||25 Mar 2010||Chung Shih||Biodegradable block copolymeric compositions for drug delivery|
|US20100076147 *||14 Nov 2007||25 Mar 2010||Suprapolix B.V.||Supramolecular polymers from low-melting, easily processable building blocks|
|US20100233264 *||5 Sep 2008||16 Sep 2010||Sungkyunkwan University Foundation For Corporate Collaboration||TEMPERATURE AND pH-SENSITIVE BLOCK COPOLYMER HAVING EXCELLENT SAFTY IN VIVO AND HYDROGEL AND DRUG DELIVERY SYSTEM USING THEREOF|
|US20110034641 *||19 Oct 2010||10 Feb 2011||Suprapolix B.V.||Preparation of supramolecular polymers containing quadruple hydrogen bonding units in the polymer backbone|
|US20110229724 *||6 Jul 2009||22 Sep 2011||Suprapolix B.V.||High flow supramolecular compounds|
|DE10005433B4 *||8 Feb 2000||4 Nov 2004||Kunio Matsumoto Takaoka||Biomaterialien|
|EP0752840A1 *||24 Mar 1995||15 Ene 1997||E.R. SQUIBB & SONS, INC.||Thermoplastic hydrogel impregnated composite material|
|EP1988108A1||26 Mar 2008||5 Nov 2008||Sungkyunkwan University Foundation for Corporate Collaboration||Temperature and pH-sensitive block copolymer having having excellent gel strength, method of preparing the same, and drug delivery system using the same|
|EP2286791A1||23 Dic 2004||23 Feb 2011||Durect Corporation||Polymeric implants, preferably containing a mixture of PEG and PLG, for controlled release of active agents, preferably a GnRH|
|EP2343342A1||23 Mar 2007||13 Jul 2011||SupraPolix B.V.||Strong reversible hydrogels|
|WO1999007343A1 *||8 Ago 1998||18 Feb 1999||University Of Utah Research Foundation||Injectable biodegradable block copolymer gels for use in drug delivery|
|Clasificación de EE.UU.||424/85.4, 514/772.3, 424/499, 424/422, 514/6.5, 514/10.8, 514/11.9, 514/12.3, 514/11.3, 514/7.6, 514/9.8, 514/12.5, 514/11.2, 514/11.6, 514/11.7, 514/12.8, 514/18.5, 514/10.9, 514/9.7, 514/10.3, 514/11.5, 514/11.1, 514/5.9, 514/21.6|
|Clasificación internacional||A61K9/70, C08G63/82, A61K9/16, A61K9/22, A61K9/00, C08G63/00, A61K47/34, A61K39/00, A61K38/17, C08G64/00, A61K9/20, A61K38/22, C08G69/10, A61K38/46, A61K47/30, A61K38/04, A61K38/00, A61L15/16, A61K38/21, C08G69/00, C08G63/08, A61K39/395, C08G81/00, A61F13/00|
|Clasificación cooperativa||A61K9/1647, A61K9/204, A61K9/0024, C08G63/00, A61K9/7007|
|Clasificación europea||A61K9/70B, A61K9/00M5D, C08G63/00, A61K9/20H6D4, A61K9/16H6D4|
|9 Dic 1993||FPAY||Fee payment|
Year of fee payment: 4
|5 Ene 1998||FPAY||Fee payment|
Year of fee payment: 8
|28 Dic 2001||FPAY||Fee payment|
Year of fee payment: 12